2-pyrazolyl-benzophenones

ABSTRACT

2-Pyrazolyl-benzophenones, e.g. those of the formula ##STR1## R = H or alkyl R o  = H, alkyl, (HO, alkoxy, amino)-alkyl, aralkyl, or aryl 
     R&#39;, r&#34; = h, alkyl, alkoxy, halo or CF 3   
     Am = open or cyclic amino 
     Corresponding ketals, or therapeutically useful acid addition salts thereof exhibit antianxiety and antidepressant effects.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of application Ser. No. 608,796, filedAug. 28, 1975 now U.S. Pat. No. 4,022,800, which in turn is acontinuation-in-part of application Ser. No. 475,475, filed June 3,1974, now U.S. Pat. No. 3,939,271.

SUMMARY OF THE INVENTION

The present invention concerns and has for its object the provision ofnew 2-(3- or 5-pyrazolyl)-benzophenones or -thiophenones, their ketalsor carbinols corresponding to Formulae I and II ##STR2## wherein Ph is a1,2-phenylene radical, Ar is a monocyclic, carbocyclic aryl radical, R₀is hydrogen, lower alkyl, (hydroxy, lower alkoxy or Am)--G_(m) H_(2m) orAr--C_(n) H_(2n), Am is an open or cyclic amino group, m is an integerfrom 1 to 7, n such from 0 to 7, each of R₁, R₂ and R₃ is hydrogen orlower alkyl, and X is oxo, thio, or hydrogen and hydroxy or loweralkoxy; a simple or mixed, open or cyclic lower alkyl or alkylene ketalthereof; or a lower alkanoyl, alkoxycarbonyl, AmCO or AmCS derivative ofthe compounds containing at least one hydrogen attached to oxygen ornitrogen; or a therapeutically useful acid addition salt thereof; aswell as of corresponding pharmaceutical compositions and of methods forthe preparation and application of these products, which are usefulantianxiety and antidepressant agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The 1,2-phenylene radical Ph, as well as the aryl radical Ar, areunsubstituted or substituted by one or more than one, preferably by oneor two, of the same or different substituents selected from the groupconsisting of lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl;etherified or esterified hydroxy, such as lower alkoxy, e.g. methoxy,ethoxy, n- or i-propoxy or -butoxy; or halo, e.g. fluoro, chloro orbromo; or trifluoromethyl. The term "lower", referred to above andhereinafter in connection with organic radicals or compoundsrespectively, defines such with up to 7, preferably up to 4, carbonatoms.

Preferred 1,2-phenylene radicals Ph are 1,2-phenylene, (loweralkyl)-1,2-phenylene, (lower alkoxy)-1,2-phenylene, (halo)-1,2-phenyleneor (trifluoromethyl)-1,2-phenylene and preferred aryl radicals Ar arephenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl mono- ordi-(halo)-phenyl or (trifluoromethyl)-phenyl.

The radical R₀ preferably represents hydrogen, lower alkyl or Ar--C_(n)H_(2n), wherein n is an integer from 0 to 7, preferably 1 to 4. It mayalso represent (hydroxy, lower alkoxy or Am)--C_(m) H_(2m) wherein m isan integer from 1 to 7 and Am is exemplified by amino, mono- or di-loweralkylamino, lower alkyleneimino or mono-aza-, oxa- or thiaalkyleneimino,wherein the additional nitrogen, oxygen or sulfur atom is separated fromthe imino-nitrogen by at least 2 carbon atoms, e.g. mono- or di-(methyl, ethyl, n- or i-propyl or -butyl)-amino; pyrrolidino, piperidinoor hexamethyleneimino; piperazino, 4-(lower alkyl, e.g. methyl orethyl)-piperazino; morpholino or thiamorpholino. Preferred amino groupsAm are mono- or di-lower alkylamino, pyrrolidino, piperidino,piperazino, 4-(lower alkyl)-piperazino or morpholino.

The radicals R₁, R₂ and R₃ represent preferably a hydrogen atom, butalso lower alkyl, above all methyl.

The ketals of said benzophenones or -thiophenones are either simpleketals or thioketals, or mixed ketals, containing oxygen and sulfur, andare derived either from lower alkanols or -thiols, or lower alkyleneglycols or thioglycols respectively. Thus, X represents, for example,two members selected from methoxy, ethoxy, n- or i-propoxy, methyl- orethylmercapto; or one member of 1,2-ethylenedioxy, 1,2- or1,3-propylenedioxy or -thioxy.

Said acyl derivatives are either esters of said carbinols and/or amidesof said primary or secondary Am-compounds, and the lower alkanoylderivatives are exemplified by formyl, acetyl, propionyl or pivalylderivatives; lower alkoxycarbonyl derivatives by methoxy-, ethoxy-, n-or i-propoxy- or -butoxycarbonyl derivatives; and AmCO and AmCSderivatives are preferably those of NH-compounds.

The compounds of the invention exhibit valuable pharmacologicalproperties, for example, antianxiety and especially antidepressanteffects, differing from those of imipramine. This can be demonstrated inanimal tests, using advantageously mammals, such as mice, rats ormonkeys, as test objects. The compounds of the invention can be appliedto the animals enterally, e.g. orally, or parenterally, such assubcutaneously or intraperitoneally, e.g. in the form of aqueoussolutions or starchy suspensions. The dosage may range between about 0.1and 300 mg/kg/day, preferably between about 1 and 100 mg/kg/day,advantageously between about 2 and 20 mg/kg/day. An antidepressanteffect is observed, for example, in the amphetamine interaction test (P.Carlton, Psychopharmacologia 1961, Vol II, p. 364) performed with malealbino rats, which are trained to press a bar every 30 seconds, in orderto avoid an electric shock applied through the floor grid. In case theanimals receive i.p. 0.25 mg/kg/day of amphetamine, their performingrate for avoiding said shocks during a test period or about 4-5 hours isslightly higher than that of placebo (saline) treated animals. In casethe animals receive the compounds of the invention (or imipramine forcontrol purposes) in the above-mentioned doses, preferably at 5 or 10mg/kg/day i.p. and about 45 minutes later the amphetamine, their rate ofavoiding the shocks is highest, as compared with that of rats receiving(a) saline alone, (b) saline and amphetamine, or (c) the compounds ofthe invention and saline. In addition the compounds of the inventionexhibit antianxiety effects in rats or squirrel monkeys, advantageouslyat dosages between about 2 and 20 mg/kg/day. Accordingly, they reduceacquired fear or anxiety associated with a psychological conflict. It isestablished by simultaneously rewarding with food and punishing withelectric shock all lever-pressing responses of the animals made in thepresence of a discriminative tone stimulus. For example, rats firstlearn to press a lever to obtain a milk reward, which is delivered onthe average of once per two minutes. After this schedule, which lastsfifteen minutes, a tone stimulus of three minute duration is presented.This stimulus signals a change from a variable interval schedule ofreinforcement, to a continuous reinforcement schedule (CRF). During theCRF schedule, all lever responses not only produce milk rewards but alsoan electric shock to the animals' feet. During the period in which ashock accompanies the food reward, the tone stimulus produces asuppression of all lever pressing responses. Thus, for example,administration of5-chloro-2-(1-methyl-4-aminomethyl-5-pyrazolyl)-2'-fluorobenzophenonemonophosphate, a characteristic compound of the invention applied atabout 5 mg/kg/day intraperitoneally to rats or orally to squirrelmonkeys, reinstate these responses, indicating that the animals toleratemore shocks in obtaining the food reinforcement. Accordingly, thecompounds of the invention are especially useful in combattingdepression and anxiety. Moreover, they are also valuable intermediatesin the preparation of other useful products, especially ofpharmacologically active compounds.

Particularly useful are compounds of Formulae I and II, in which Ph is1,2-phenylene, (lower alkyl)-1,2-phenylene, (loweralkoxy)-1,2-phenylene, (halo)-1,2-phenylene or(trifluoromethyl)-1,2-phenylene, Ar is H-Ph, R₀ is hydrogen, loweralkyl, (hydroxy, lower alkoxy or Am)--C_(m) H_(2m), or Ar--C_(n) H_(2n),Am is amino, mono- or di-lower alkylamino, or five to sevenring-membered lower alkyleneimino, m is an integer from 2 to 4, and nsuch from 0 to 4, each of R₁, R₂ and R₃ is hydrogen or lower alkyl and Xis oxo, thio, or hydrogen and hydroxy or lower alkoxy, or the simple ormixed, open or cyclic lower alkyl or alkylene ketals thereof, or loweralkanoyl, alkoxy-carbonyl, AmCO or AmCS derivatives of the compoundscontaining at least one hydrogen attached or oxygen or nitrogen, or atherapeutically useful acid addition salt thereof.

Preferred compounds of the invention are those of Formula I and II,wherein Ph is 1,2-phenylene, (alkyl)-1,2-phenylene or(halo)-1,2-phenylene, Ar is H-Ph, R₀ is hydrogen, alkyl, 2- or3-(hydroxy or dialkylamino)-(ethyl or propyl) or H-Ph-methyl, each ofR₁, R₂ and R₃ is hydrogen or methyl, the group Am is amino ordialkylamino, X is oxo, thio, two alkoxy groups, one alkoxy andalkylmercapto group, or ethylenedioxy, or an alkanoyl derivative of thecompounds containing at least one hydrogen attached to oxygen ornitrogen, in which compounds alkyl, alkanoyl, alkoxy or alkylmercaptohas up to 4 carbon atoms, or a therapeutically useful acid addition saltthereof.

Outstanding are the compounds of Formulae III and IV ##STR3## wherein Ris hydrogen or methyl, R⁰ is hydrogen, methyl, ethyl, n- or i-propyl,n-, i- or t-butyl, 2- or 3-(hydroxy, dimethylamino ordiethylamino)-(ethyl or propyl) or benzyl, each of R' and R" ishydrogen, methyl, fluoro or chloro and Am' is amino, dimethylamino ordiethylamino, the methyl or ethylene ketal or thioketal, or atherapeutically useful acid addition salt thereof.

The compounds of this invention are prepared according to conventionalmethods, for example by converting in compounds of Formulae Va or b##STR4## in which Y is a substituent capable of being converted into R₂,##STR5## Y into said α-aminoalkyl group and, if desired, converting anyresulting compound into another compound of the invention.

The substituent Y is, for example, a reactively esterifiedα-hydroxy-alkyl group, preferably such derived from a strong inorganicmetalloidic acid, particularly a hydrohalic acid, e.g. hydrochloric orhydrobromic acid or sulfuric acid, or an organic sulfonic acid, such asa lower alkane or benzene sulfonic acid, e.g. methane, ethane, benzeneor p-toluene sulfonic acid, or an α-phosphonium-alkyl group, e.g. anα-triphenyl-phosphonium halide-alkyl group. Said groups Y are convertedinto α-Am-alkyl by condensation with H-Am or an alkali metal, e.g.sodium salt thereof.

Another substituent Y is, for example, an α-(nitro, oximino orimino)-alkyl group, or preferably a cyano or carbamoyl group, e.g.CO-Am, which groups can be converted into α-Am-alkyl by reduction. Theabove nitro compounds, nitriles or amides are advantageously reducedwith the use of simple or complex light metal hydrides, such as boronhydride or alkali metal aluminum hydrides, e.g. lithium aluminumhydride. The above oximes or Schiff's bases, i.e. said α-oximino- oriminoalkyl compounds, as well as the α-nitroalkyl or cyano compounds,can also be reduced with catalytically activated or nascent hydrogen,such as hydrogen in the presence of nickel, platinum or preferablypalladium catalysts, or generated electrolytically or by the action ofmetals on compounds with active hydrogen, such as acids or alcohols,e.g. zinc or iron and inorganic or organic acids, such as hydrohalic orlower alkanoic acids, or sodium or aluminum or their amalgams and loweralkanols.

Another process for the preparation of the compounds of Formulae I andII consists in hydrolyzing compounds of Formulae Vc or d ##STR6## and,if desired, converting any resulting product into another compound ofthe invention.

Hydrolysis is advantageously performed under mildly acidic conditions,e.g. in the presence of aqueous and/or alkanolic acids, e.g. saidmetalloidic acids, or the therapeutically useful acids listed below.

The carbinols of the invention (X=H+OH) are obtained from the ketones(X=O) by reduction as shown for the amides, advantageously with complexborohydrides, e.g. sodium boro- or lithium borohydride, or aluminumhydrides, e.g. lithium aluminum hydride in protic or non-proticsolvents.

Another process for the preparation of the compounds of Formulae I andII consist in condensing a ketal or ether of Formula Ve ##STR7## whereinX' is said X different from O, S or H+OH and Am" is said Am differentfrom a primary or secondary amino group, with R₁ --NH--NH₂ and ifdesired, converting any resulting compound into another compound of theinvention.

The substituent X' is preferably lower alkoxy and alkylmercapto and Am"preferably di-lower alkylamino. Said condensation is advantageouslyperformed at elevated temperatures, for example between about 30° and150° and in the presence or absence of a lower alkanol.

The compounds thus obtained can be converted into each other accordingto conventional methods. For example, resulting compounds containing atleast one hydrogen atom attached to oxygen or nitrogen can be acylated,for example, with the use of reactive functional derivatives of thecorresponding acids, such as halides or anhydrides thereof, e.g. acetylor propionyl chloride, lower alkyl chloroformates, carbamoyl orthiocarbamoyl chlorides; acetic anhydride, ketene, isocyanates orisothiocyanates. Said primary or secondary amines can also be reactedwith reactives esters of the respective alcohols, preferably derivedfrom hydrohalic, aliphatic or aromatic sulfonic acids, e.g. lower alkylor aralkyl chlorides, bromides, iodides; alkane- or benzenesulfonates,e.g. the mesylate or tosylate, or with corresponding aldehydes orketones and reducing agents, e.g. formic acid, in order to obtain sec.or tert. amines respectively. Resulting ketals can also be convertedinto the ketone or thioketones, for example, by treating them withacidic agents, such as the above inorganic or organic acids. Finally, aresulting base can be converted into a corresponding acid addition salt,preferably with the use of a therapeutically useful acid or anionexchange preparation, or resulting salts can be converted into thecorresponding free bases, for example, with the use of a base, such as ametal hydroxide, basic salt, ammonia, amine or cation exchangepreparation, e.g. an alkali metal hydroxide or carbonate. Said acidaddition salts are preferably such of therapeutically useful inorganicacids, such as strong metalloidic acids, for example hydrohalic, e.g.hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric orperchloric acid; aliphatic or aromatic carboxylic or sulfonic acids,e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic,phenylacetic, benzoic 4-aminobenzoic, anthranilic, 4-hydroxybenzoic,salicylic, 4-aminosalicylic, embonic, nictinic; methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic,halogen-benzenesulfonic, toluenesulfonic, naphthalenesulfonic orsulfanilic acid.

These or other salts, for example, the picrates, can also be used forpurification of the bases obtained; the bases are converted into salts,the salts are separated and the bases are liberated from the salts. Inview of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances. Resulting mixtures ofisomers can be separated into the single isomers by methods inthemselves known, e.g. by fractional distillation, crystallizationand/or chromatography.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Mainlythose starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being especially valuable.

The starting material Vc to d is new and is considered as additionalsubject matter of the present invention. It is prepared according to thefollowing formula scheme, which is illustrated by the examples herein:##STR8##

Another version for preparing the starting material of the formula Va orVb is as follows: ##STR9##

A modification of the above process for the manufacture of theintermediates of the formula XXX from a compound of the formula XXIX maybe carried out as follows: ##STR10##

A process for the manufacture of a tautomer of an intermediate of theformula XXXIV, in which R_(o) is hydrogen, is the following one:##STR11##

In a compound of the formula XLI, the hydrogen attached to thering-nitrogen may be substituted by any of the organic residuesspecified for R_(o) ; this substitution reaction is carried out aspreviously shown for compounds of the formulae I or II. In a compound ofthe formula XL, the imino nitrogen may be quaternized by treatment witha reactive ester of an alcohol, such as a lower alkyl fluorosulfonate,tri-lower alkyl-oxonium tetrafluoroborate and the like, followed by acidhydrolysis, whereby an intermediate of the formula XXXIV is obtained, inwhich R_(o) is the residue of an alcohol. Alternatively, a compound ofthe formula XLI may be treated with a derivative of acrylic acid, suchas acrylonitrile or a lower alkyl acrylate, in the N-Michael-additionproduct the imino nitrogen is then quaternized as previously shown orwith another reactive ester of an alcohol, such as a lower alkyl halide,and the quaternary compound is then treated with a base, such as atertiary amine or an alkali metal hydroxide or lower alkoxide in orderto furnish a compound of the formula XXXIV, wherein R_(o) is the residueof an alcohol.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, enzymes of the binders oreffervescent mixtures and/or (e) absorbents, colorants, flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously fattyemulsions or suspensions. They may be sterialized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. They may also contain other therapeutically valuablesubstances. Said pharmaceutical compositions are prepared according toconventional mixing, granulating or coating methods respectively andcontain about 0.1 to 75%, preferably about 1 to 50% of the activeingredient.

The following examples, illustrating the invention, are not to beconstrued as being limitations thereon. Temperatures are given indegrees Centrigrade and all parts wherever given are parts by weight.

EXAMPLE 1

The mixture of 130 mg of5-chloro-2-(1-methyl-4-methoxyiminomethyl-5-pyrazolyl-2'-fluorobenzophenoneethylene ketal, 25 ml of diethyl ether and 100 mg of lithium alluminumhydride is stirred at room temperature for 16 hours. Thereupon 0.1 ml ofwater, 0.1 ml of 15% aqueous sodium hydroxide and 0.3 ml of water areadded, the mixture filtered and the filtrate extracted with Nhydrochloric acid. The acidic layer is separated, made basic with 2Naqueous sodium hydroxide, extracted with methylene chloride, the extractdried and evaporated, to yield the5-chloro-2-(1-methyl-4-aminomethyl-5-pyrazolyl)-2'-fluorobenzophenoneethylene ketal of the Formula IV, wherein R=H, Am'=NH₂, R^(o) =CH₃, R'=Fand R"=Cl, showing in the NMR-spectrum a singlet at δ=3.03 and a tripletat δ=8.0 ppm.

The mixture of 100 mg thereof, 10 ml of dioxane and 10 ml of 2Nhydrochloric acid is refluxed for 1 hour under nitrogen and the dioxaneevaporated. The aqueous solution is cooled, admixed to methylenechloride, made basic with 2N aqueous sodium hydroxide and extracted withdiethyl ether. The extract is dried, filtered into the solution of 50 mgof phosphoric acid in 1 ml of ethanol and the precipitate filtered off,to yield the5-chloro-2-(1-methyl-4-aminomethyl-5-pyrazolyl)-2'-fluorobenzophenonemonophosphate melting at 180°.

The starting material is obtained as follows: The solution of 10 g of5-chloro-2'-fluoro-2-phenylmercaptomethyl-benzophenone ethylene ketal(Example 2) in 50 ml of methyl iodide is refluxed under nitrogen for 5days. It is evaporated and the formed methyl phenyl tnioether distilledoff at 60°/0.1 mm Hg, to yield the5-chloro-2'-fluoro-2-iodomethyl-benzophenone ethylene ketal.

The mixture of 9.6 g thereof, 5 g sodium bicarbonate and 50 ml ofdimethylsulfoxide is stirred for 20 minutes at 110°, cooled and pouredonto ice. The mixture is extracted with diethyl ether, the extractwashed with water and saturated aqueous sodium chloride, dried,evaporated and the residue recrystallized from diethyl ether-hexane, toyield the 5-chloro-2'-fluoro-2-formylbenzophenone ethylene ketal meltingat 103°-105°.

To the solution of 1.6 g thereof in 60 ml of diethyl ether, 3 ml of 2.3molar methyl lithium in diethyl ether are added while stirring andcooling with ice. After 5 minutes 20 ml of water are added cauteously,the organic layer separated, washed with saturated aqueous sodiumchloride, dried and evaporated, to yield the5-chloro-2'-fluoro-2-(1-hydroxy-ethyl)-benzophenone ethylene ketalshowing in the NMR-spectrum a doublet a δ=1.1 ppm (indeuterochloroform).

To the solution of 1.8 g thereof in 100 ml of diethyl ether, 25 ml ofthe solution (obtained from 100 g of sodium dichromate dihydrate, 300 mlof water, 136 ml of concentrated sulfuric acid and diluting it withwater to 500 ml) are added while stirring. After 40 minutes the mixtureis poured on ice, the organic phase separated and washed with aqeuoussodium bisulfite, water, aqeuous sodium bicarbonate and saturatedaqueous sodium chloride. It is dried and evaporated, to yield the2-acetyl-5-chloro-2'-fluorobenzophenone ethylene ketal showing in theNMR spectrum a singlet at δ=2.4 ppm.

The mixture of 1.1 g thereof and 7 ml of dimethyl formamidedimethylacetal is refluxed for 16 hours and evaporated under reducedpressure, to yield the5-chloro-2-(3-dimethylaminoacryloyl)-2'-fluoro-benzophenone ethyleneketal showing in the NMR-spectrum a broad singlet at δ=2.7 ppm.

The mixture of 1.3 g thereof, 0.3 g of methylhydrazine and 25 ml ofethanol is refluxed for 7 hours under nitrogen and evaporated. Theresidue is chromatographed on silica gel and the column eluted firstwith benzene, then diethyl ether and the ether eluate collected, toyield the 5-chloro-2'-fluoro-2-(1-methyl-5-pyrazolyl)-benzophenoneethylene ketal showing in the NMR-spectrum a singlet at δ=3.1 and adoublet at δ=5.95 ppm.

The solution of 650 mg thereof in 2.7 ml of ethylene dichloride is addeddropwise to the complex, prepared from 265 mg of dimethylformamide and555 mg of phosphorus oxychloride, while cooling with ice, and dissolvedin 1.8 ml of ethylene dichloride, while stirring and the mixture isrefluxed for 2 hours under nitrogen. After cooling the solution of 2.45g of sodium acetate trihydrate in 3.6 ml of water is added and themixture refluxed for 15 minutes. It is diluted with methylene chlorideand water, the organic layer separated and dried, to yield the5-chloro-2'-fluoro-2-(1-methyl-4-formyl-5-pyrazolyl)-benzophenoneethylene ketal, showing in the NMR-spectrum a band at δ=9.13 ppm.

The mixture of 660 mg thereof, 3 ml of pyridine and 170 mg ofO-methyl-hydroxylamine hydrochloride is stirred for 16 hours at roomtemperature and evaporated under reduced pressure. The residue is takenup in chloroform and the solution filtered through a short column ofsilica gel, to yield the desired methoxime.

EXAMPLE 2

The mixture of 3.25 g of8-chloro-6-(2-fluorophenyl)-1-methyl-1H,4H-pyrazolo-[4,3-d](2)benzazepine,100 ml of 0.5N sulfuric acid and 15 ml of ethanol is stirred undernitrogen at room temperature for 2 days. The resulting solution iscooled to 0°, transferred into a separatory funnel, made basic withice-cold 30% aqueous sodium hydroxide and quickly extracted with diethylether. The extract is dried filtered into the mixture of 1.2 g of 85%phosphoric acid and 50 ml ethanol and the precipitate collected, toyield the monophosphate identical with that of Example 1, m.p. 180°.

Analogously the5-chloro-2-(1-methyl-4-aminomethyl-5-pyrazolyl)-benzophenone monooxalateis obtained, melting at 163°-165°.

The starting material is prepared as follows: The solution of 141 g ofα,p-dichlorotoluene in 200 ml tetrahydrofuran is added dropwise to anice-cold saturated solution of dimethylamine in 1 liter oftetrahydrofuran and the mixture stirred for 2 days at 25°. It is dilutedwith diethyl ether, washed with 2N aqueous sodium hydroxide, the organiclayer dried, evaporated, the residue distilled and the fraction boilingat 106°/12 mm Hg collected, to yield theN,N-dimethyl-4-chlorobenzylamine.

To the solution of 81.6 g thereof in 1.5 lt of diethyl ether 360 ml of1.6 molar n-butyl lithium in hexane are added dropwise while stirring at0°-5° under nitrogen. After 3 hours the solution of 58 g of2-fluorobenzonitrile in 1.5 lt of diethyl ether is added dropwise whilestirring, the mixture refluxed for 3 hours and stirred at roomtemperature for 16 hours. Thereupon crushed ice and 265 ml of 5Nhydrochloric acid are added, the mixture refluxed for 1/2 hour, cooledand the aqueous layer separated. It is made basic with 30% aqueoussodium hydroxide, extracted with methylene chloride, the extract dried,evaporated and the residue dried in a high vacuum at 100°, to yield the5-chloro-2'-fluoro-2-dimethylaminomethyl-benzophenone melting at91°-92°.

To the solution of 138 g thereof in 3.2 lt of methylene chloride, thatof 55 g of cyanogen bromide in 300 ml of methylene chloride is addeddropwise while stirring and cooling with ice. After stirring overnight,the mixture is evaporated under reduced pressure at 40°. The residue istaken up in 2.4 lt of methanol. 56.8 ml of thiophenol are added,followed by 596 ml of N methanolic sodium hydroxide, the mixture stirredfor 2 hours at 0° and overnight at room temperature. It is cooled again,filtered and the residue washed with methanol, to yield the5-chloro-2'-fluoro-2-phenylmercaptomethyl-benzophenone melting at81°-82°.

The mixture of 144.6 g thereof, 386 g of p-toluenesulfonic acid, 800 mlof ethylene glycol and 3 lt of benzene is refluxed at the waterseparator for 19 days and evaporated under reduced pressure, to yieldthe corresponding ethylene ketal melting at 69°.

To the solution of 24.2 g thereof in 285 ml of dry tetrahydrofuran, 46.2ml of 1.6 molar n-butyl lithium in hexane are added while stirring undernitrogen at -67° to -70°. After one hour 100 ml of 6 molar ethyleneoxidein tetrahydrofuran are added during five minutes, the temperatureallowed to rise to -35° and the mixture stirred for two hours at roomtemperature. It is evaporated under reduced pressure, the residue takenup in 165 ml of dioxane, 165 ml of 2N hydrochloric acid are added andthe mixture refluxed for one hour. It is concentrated under reducedpressure to about half its volume, the concentrate extracted withmethylene chloride, the extract dried and evaporated, to yield the5-chloro-2-(3-hydroxy-1-phenylmercaptopropyl)-2'-fluorobenzophenone.

To the mixture of 26 g thereof, 16 ml of N,N-diisopropylethylamine and360 ml of diethyl ether, 9.2 ml of methanesulfonyl chloride are addeddropwise while stirring at 0°. After 16 hours the mixture is washed withice cold 5% hydrochloric acid, ice water and ice cold aqueous sodiumcarbonate, dried and evaporated under reduced pressure and below 30°.The residual methanesulfonate is taken up in 220 ml of methanol,saturated with ammonia, while stirring and after two hours the solutionis again saturated with ammonia. It is allowed to stand at roomtemperature for 27 days, the precipitate (B) formed filtered off and thefiltrate evaporated. The residue is taken up in diethyl ether, thesolution extracted with 2N sulfuric acid, the aqueous solution madebasic with 30% aqueous sodium hydroxide and extracted with methylenechloride. The extract is dried, evaporated, the residue combined with(B) and recrystallized from acetone, acidified with ethereal hydrogenchloride to yield the8-chloro-1-(2-fluorophenyl)-5-phenylmercapto-3,4-dihydro-2-benzazepinehydrochloride melting at 184°-185°.

The solution of 34.8 g thereof in 340 ml of methylene chloride iscombined with 300 ml of 1.25 molar triethyloxonium tetrafluoroborate inmethylene chloride while stirring under nitrogen. After 68 hours themixture is evaporated under reduced pressure, the residue dissolved in500 ml or dimethylsulfoxide and the solution stirred under nitrogen at55° for 6 hours. It is evaporated under reduced pressure, the residuetaken up in diethyl ether, the solution washed with water and extractedwith 5% hydrochloric acid. The pH of the acidic solution is adjusted to8 with sodium carbonate and the mixture extracted with diethyl ether.The extract is washed with water and saturated aqueous sodium chloride,the washings re-extracted with diethyl ether, the combined extractsdried, evaporated and the residue recrystallized from diethyl ether withthe aid of charcoal, to yield the8-chloro-1-(2-fluorophenyl)-3,4-dihydro-2-benzazepin-5-one melting at107°-109°.

The mixture of 3.4 g thereof and 275 ml ofdimethylformamide-dimethylacetal is refluxed for 75 minutes and theexcessive reagent removed under reduced pressure at a temperature notexceeding 135°. The residue is crystallized from diethyl ether, to yieldthe8-chloro-4-dimethylamino-methylidene-1-(2-fluorophenyl)-3,4-dihydro-2-benzazepin-5-onemelting at 224°-226°.

2 g thereof are added to the solution of 0.7 g of methylhydrazine in 100ml of ethanol, the mixture refluxed for 45 minutes and evaporated underreduced pressure. The residue is recrystallized from ethylacetate-hexane, to yield the8-chloro-6-(2-fluorophenyl)-10a-hydroxy-1-methyl-3a,10a-dihydro-1H,4H-pyrazolo[4,3-d](2)benzazepinemelting at 114°-115°.

The solution of 1.74 g thereof in 60 ml of chloroform is stirred with100 ml of 0.1 N hydrochloric acid for 15 minutes, the pH of the aqueousphase adjusted to 8 with aqueous sodium carbonate and the mixture againstirred for 5 minutes. The organic layer is separated, dried, evaporatedand the residue recrystallized from diethyl ether-hexane, to yield the8-chloro-6-(2-fluorophenyl)-1-methyl-1H,4H-pyrazolo[4,3-d](2)benzazepine melting at 128°-130°. The correspondingdihydrochloride melts at 190° with decomposition.

EXAMPLE 3

The solution of 13 g of8-chloro-6-(2-fluorophenyl)-1-methyl-1H,4H-pyrazolo [4,3-d](2)benzazepine in 50.7 g of formic acid and 31.2 ml of 37% aqueousformaldehyde is refluxed for 10 hours. It is evaporated under reducedpressure, the residue taken up in methylene chloride and poured on iceand excess 30% aqueous sodium hydroxide. Separation of the organiclayer, drying and removal of the solvent results in a solid productwhich, on neutralization of an acetone solution with ethereal hydrogenchloride, yields the5-chloro-2-(1-methyl-4-dimethylaminomethyl-5-pyrazolyl)-2'-fluorobenzophenonehydrochloride melting at 225°-227°.

EXAMPLE 4

The solution of 1.86 g of5-chloro-2-(1-methyl-4-dimethylaminomethyl-5-pyrazolyl)-2'-fluorobenzophenonein 100 ml of ethanol is stirred for 21/2 hours at room temperature with500 mg sodium borohydride. It is evaporated under reduced pressure andthe residue shaken with methylene chloride and 5% aqueous sodiumhydroxide. After drying the organic layer and removal of the solvent,the residue is crystallized from diethyl ether-hexane, to yield theα-[5-chloro-2-(1-methyl-4-dimethylaminomethyl-5-pyrazolyl)-phenyl]-2-fluorobenzylalcohol melting at 125° to 127°; the hydrochloride thereof melts at225°-230°.

EXAMPLE 5

Preparation of 10,000 tablets each containing 25 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        5-chloro-2-(1-methyl-4-aminomethyl-5-                                         pyrazolyl)-2'-fluorobenzophenone                                              mono-phosphate         250.00     g                                           Lactose                1,956.00   g                                           Corn starch            90.00      g                                           Polyethylene glycol 6,000                                                                            90.00      g                                           Talcum powder          90.00      g                                           Magnesium stearate     24.00      g                                           Purified water         q.s.                                                   ______________________________________                                    

Procedure:

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance, lactose, talcum, magnesium stearate and half ofthe starch are mixed in a suitable mixer. The other half of the starchis suspended in 45 ml of water and the suspension added to the boilingsolution of the polyethylene glycol in 180 ml of water. The paste formedis added to the powders which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35°,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 7.1 mm diameter, uppers bisected.

Preparation of 10,000 capsules each containing 10 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        5-chloro-2-(1-methyl-4-aminomethyl-5-                                         pyrazolyl)-2'-fluorobenzophenone                                              mono-phosphate         500.0      g                                           Lactose                2,350.0    g                                           Talcum powder          150.0      g                                           ______________________________________                                    

Procedure:

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance is placed in a suitable mixer and mixed firstwith the talcum, then with the lactose until homogenous. No. 2 capsulesare filled with 300 mg of the mixture, using a capsule filling machine.

EXAMPLE 6

A solution of 0.208 g of3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-2-methyl-4-phthalimidomethyl-pyrazolein 2 ml of concentrated hydrochloric acid and 2 ml of water is refluxedfor 16 hours under an atmosphere of nitrogen. The solution is cooledwith ice, made alkaline by adding a 15% aqueous sodium hydroxidesolution and the product is extracted with methylene chloride. Theorganic layer is dried over anhydrous sodium sulfate and the solvent isevaporated to give a residue consisting of a mixture of8-chloro-6-(2-fluoro-phenyl)-1-methyl-1H,4H-pyrazolo[4,3-d](2)benzazepineand mainly of the5-chloro-2-(1-methyl-4-aminomethyl-5-pyrazolyl)-2'-fluorobenzophenone.Conversion of said residue into its phosphate as shown in Example 1yields the identical compound melting at 180°.

The starting material is prepared as follows: To a mixture of 1250 ml ofa 40% aqueous solution of methylamine and 1250 ml of methylene chloride,cooled in an ice bath, is added with stirring a solution of 500 g of4-chlorobenzoyl chloride in 625 ml of methylene chloride. After theaddition (50 minutes), the mixture is stirred for an additional 2 hours.The white precipitate is filtered off and air dried and the methylenechloride layer of the filtrate is dried and evaporated to give the crude4-chloro-N-methyl-benzamide, which, after crystallization from 1200 mlof methanol, melts at 158°-161°; an additional amount of the product isrecovered from the mother liquor, m.p. 158°-160°.

In a 3-necked flask equipped with thermometer, nitrogen inlet anddropping funnel, 84.75 g of 4-chloro-N-methylbenzamide is dissolved in3000 ml of dry tetrahydrofuran and cooled to -45° while stirring under anitrogen atmosphere. When this temperature is reached, 660 ml of a 1.6molar solution of n-butyl-lithium in hexane are added at such a rate,that the temperature does not exceed -40°. After the addition iscomplete, the cooling bath is removed and the temperature is allowed toraise to +10°. The mixture is then cooled in an ice bath and 65.6 g of2-fluoro-benzaldehyde in 100 ml tetrahydrofuran is added in one batch.The bath is removed and the mixture is then stirred at room temperaturefor 21/4 hours; the pinkish color of the precipitate changes to a lightgrey. The flask is cooled again, 160 ml of methyl iodide is added andthe reaction mixture is stirred at room temperature for 68 hours. Thetetrahydrofuran is then removed under reduced pressure, the residue istaken up in about 1000 ml of diethyl ether and shaken with a mixture ofice water. After separation, the organic layer is washed with asaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. The aqueous layers are reextracted with an additionalportion of diethyl ether. Removal of the solvent leaves the4-chloro-2-(2-fluoro-α-methoxy-benzyl)-N,N-dimethyl-benzamide as an oilyresidue, which is directly used in the subsequent step.

A solution of 142 g of the dry4-chloro-2-(2-fluoro-α-methoxy-benzyl)-N,N-dimethyl-benzamide in 1400 mlof toluene is cooled to -45° under an atmosphere of nitrogen. Then, asolution of 780 ml of a 1.7 molar solution of methyl lithium in diethylether is added at a rapid rate but without allowing the temperature toexceed -40°. The temperature is then allowed to slowly raise to roomtemperature. One hour after the addition of the methyl lithium, thereaction is quenched with ice/water, the organic layer is separated,washed with a saturated aqueous solution of sodium chloride and driedover anhydrous sodium sulfate. The aqueous layers are reextracted withdiethyl ether. After evaporation of all solvents, the residue iscrystallized from hexane to give the4-chloro-2-(2-fluoro-α-methoxy-benzyl)-acetophenone, m.p. 59°-61°.

A solution of 85.3 g of the4-chloro-2-(2-fluoro-α-methoxy-benzyl)-acetophenone in 370 ml of diethylcarbonate is added to a cooled (ice bath) suspension of 17.2 g of sodiumhydride (55% in mineral oil, washed with diethyl ether to free it fromthe mineral oil) in 180 ml of diethyl carbonate. After the addition, thereaction mixture is stirred at room temperature for 21/2 days, thendiluted with diethyl ether. Ice is added and the pH is adjusted to 6 byadding hydrochloric acid and an aqueous sodium dihydrogenphosphatesolution. After separation, the organic layer is washed with a saturatedaqueous solution of sodium chloride, dried over sodium sulfate andevaporated to dryness. All aqueous layers are reextracted with diethylether. The ethyl3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-phenyl]-3-oxo-propionate isobtained as a liquid residue, which is used in the next step withoutfurther purification.

A solution of 107 g of the crude ethyl3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-phenyl]-3-oxo-propionate in200 ml of dry dimethylformamide is refluxed for 1 hour with 84 ml ofdimethylformamide-dimethylacetal under an atmosphere of nitrogen. Then,all solvent and excess reagent are removed at a pressure of 12 mm Hg.The residue, consisting of ethyl3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-2-dimethylaminomethylene-3-oxo-propionateand containing some dimethylformamide, is directly used in the nextstep.

A solution of 127 g of the crude ethyl3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-2-dimethylaminomethylene-3-oxo-propionatein 1500 ml of ethanol is refluxed for 1 hour with 25 g of methylhydrazine under an atmosphere of nitrogen. Then, all solvent andvolatile reagent are removed at a pressure of 12 mm Hg, and the residueis crystallized from 400 ml of diethyl ether to give product A, m.p.128°-130°. Charcoal treatment of the mother liquor and evaporation to150 ml, provides a product B, m.p. 114°-116°. Product A represents oneisomeric (rotameric) form of the3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole,whereas product B is primarily the other isomeric (rotameric) form ofthe product, contaminated with a small amount of the first isomer.

To a solution of 20.1 g of3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazolein 250 ml methylene chloride is added 54 ml of a 1.4 molar borontrichloride solution in methylene chloride, and the mixture is stirredduring 16 hours. Ice/water is then added; the organic layer separated,washed with a saturated solution of sodium chloride and dried overanhydrous sodium sulfate. The aqueous layers are reextracted withmethylene chloride. After removal of the solvent, the3-[4-chloro-2-(α-chloro-2-fluoro-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazoleis obtained as the solid residue, which is directly used in the nextstep.

A solution of the3-[4-chloro-2-(α-chloro-2-fluoro-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazolein 200 ml of dioxane is refluxed for 4 hours with 75 ml of a 2N aqueoussolution of sodium hydroxide. The mixture is evaporated, the residue isshaken between diethyl ether and water, the basic aqueous layer isseparated and acidified with 35 ml of 5N hydrochloric acid and extractedtwice with methylene chloride. Drying of the organic layer overanhydrous sodium sulfate and evaporation of the solvent produces a foamyresidue, comprising the4-carboxy-3-[4-chloro-2-(2-fluoro-α-hydroxy-benzyl)-phenyl]-2-methyl-pyrazole,which is directly used in the subsequent step.

A solution of 20.3 g of the crude4-carboxy-3-[4-chloro-2-(2-fluoro-α-hydroxy-benzyl)-phenyl]-2-methyl-pyrazolein 500 ml of toluene is refluxed with 1 g of p-toluenesulfonic acidusing a water separator for 16 hours while stirring; the startingmaterial starts to precipitate at the beginning but redissolves onfurther refluxing. The mixture is cooled, the toluene is evaporatedusing a rotary distillation apparatus until a product starts toprecipitate. The mixture is then cooled, and a first crop of8-chloro-6-(2-fluoro-phenyl)-1-methyl-4-oxo-1H,6H-pyrazolo-[4,3-d](2)benzoxepine,m.p. 198°-200°, can be collected. The mother liquor is washed with acold aqueous solution of sodium carbonate, dried and evaporated.Crystallization of the residue from a mixture of diethyl ether andtoluene provides an additional crop of the product, m.p. 219°-220°.

The aluminum hydride used in the following step is prepared according tothe procedure described by Brown et al, J. Am. Chem. Soc., Vol. 90, page2934 (1968): mixture of 3.05 g of lithium aluminum hydride in 52 ml ofdry tetrahydrofuran is stirred for 2 hours at room temperature. Anadditional 68 ml of tetrahydrofuran are added. The mixture is cooled inan ice bath and then treated with 2.14 ml of concentrated sulfuric acid,which is added dropwise. Vigorous stirring is continued for one hour atroom temperature. The supernatant solution of the aluminum hydride isdirectly used in the following reaction.

To an ice-cooled solution of approximately 33 m moles of aluminumhydride in 50 ml of tetrahydrofuran is added a solution of 6.86 g of8-chloro-6-(2-fluoro-phenyl)-1-methyl-4-oxo-1H,6H-pyrazolo[4,3-d]benzoxepinein 150 ml of dry tetrahydrofuran under an atmosphere of nitrogen. Afterthe addition, the mixture is stirred an additional 30 minutes in an icebath. The excess of the reagent is then carefully destroyed by addingwater; 50 ml of 2N hydrochloric acid is added to dissolve the voluminousprecipitate. The two layers are separated, the organic layer is washedwith a saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate. All aqueous layers are reextracted withdiethyl ether. The residue (consisting of a mixture of thermallyinterconvertible isomers) is taken up in 100 ml of dioxane and refluxedfor 2 hours. The dioxane is then removed under reduced pressure and theresidue is crystallized from 30 ml of diethyl ether to give thethermodynamically more stable isomer of the 3-[4-chloro-2-(2-fluoro-α-hydroxy-benzyl)-phenyl]-4-hyroxymethyl-2-methyl-pyrazole,m.p. 152°-155°. The mother liquor is equilibriated again by refluxing indioxane and an additional amount of the product, m.p. 153°-155°, can becollected.

A solution of 1.04 g of3-[4-chloro-2-(2-fluoro-α-hydroxybenzyl)-phenyl]-4-hydroxymethyl-2-methyl-pyrazolein 25 ml of anhydrous tetrahydrofuran is cooled in a dry nitrogenatmosphere in an ice bath. Then, 7.15 ml of a 0.504 molar solution ofthionyl chloride in benzene is added through a dropping funnel, followedby 7.25 ml of a 0.496 molar solution of pyridine in tetrahydrofuran.After the addition, a precipitate forms, the mixture is stirred for 30minutes in the ice bath and is then treated with 20 ml of 4N aqueoussulfuric acid. The mixture is stirred for another 30 minutes in the icebath. The two layers are then separated in a separatory funnel, washedwith a concentrated solution of sodium chloride and the aqueous layersare reextracted with diethyl ether. After drying the organic layers, thesolvent is removed at a temperature of below 35°.

The residue is then dissolved in 50 ml of diethyl ether, cooled in anice bath and 5 ml of an aqueous chromic acid solution (which is preparedby dissolving 100 g of sodium dichromate dihydrate in 300 ml of water,adding 136 ml of concentrated sulfuric acid and diluting the mixture toa volume of 500 ml with water) are added while stirring. After stirringfor 30 minutes at 0°, the excess of the chromic acid is destroyed withan aqueous sodium sulfite solution. The mixture is diluted with diethylether, transferred to a separatory funnel and the two layers areseparated. After washing with water, reextraction of the aqueous layerswith diethyl ether and drying over anhydrous sodium sulfate, the solventis removed on the rotary still below 35° to give the4-chloromethyl-3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl-1-methylpyrazole,which is directly used in the next step.

A solution of 1.0 g of the crude4-chloromethyl-3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-2-methyl-pyrazolein 15 ml of dry dimethylformamide is stirred at room temperature with0.55 g of potassium phthalimide for 16 hours. The mixture is dilutedwith diethyl ether, washed twice with water and then with a saturatedaqueous sodium chloride solution. The aqueous layers are reextractedwith diethyl ether; the organic phase is dried over anhydrous sodiumsulfate. After evaporation of the solvent, the residue is dissolved in15 ml of diethyl ether, whereupon the product crystallizes. A first cropof the3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-2-methyl-4-phthalimidomethyl-pyrazole,m.p. 153°-155°, can be collected.

Alternatively the starting material is prepared as follows: A solutionof 0.347 g of3-[4-chloro-2-(2-fluoro-α-hydroxy-benzyl)-phenyl]-4-hydroxymethyl-2-methyl-pyrazole,0.278 g of trityl chloride and 0.101 g of triethylamine in 15 ml ofmethylene chloride is stirred for 16 hours at room temperature. Thesolution is then filtered through a small column of neutral aluminumoxide. The column is washed with methylene chloride and the filtrate,containing the3-[4-chloro-2-(2-fluoro-α-hydroxybenzyl)-phenyl]-2-methyl-4-trityloxymethyl-pyrazole,is used in the next step.

The above solution is added to a solution of 0.6 g of chromium trioxideand 0.95 g of pyridine in 15 ml of methylene chloride. After 15 minutesthe solution is filtered through a small column of neutral aluminumoxide; the column washed with methylene chloride and the filtrate isevaporated to dryness. Toluene is added to the residue which containssome pyridine. The toluene is removed by evaporation under reducedpressure and the residue, containing the3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-2-methyl-4-trityloxymethyl-pyrazole,is used without any further purification in the next step.

The above residue is dissolved in 15 ml of tetrahydrofuran and 4 ml ofconcentrated hydrochloric acid is added to the solution, which is thenstirred for three hours at room temperature. The solvent is removed byevaporation under reduced pressure and the residue is treated withdiethyl ether and a saturated solution of sodium bicarbonate. The ethersolution is washed with water, dried over sodium sulfate and passedthrough a column of silica gel; the triphenyl carbinol is not retainedon the column. After washing with diethyl ether, the column is elutedwith tetrahydrofuran. The solvent is removed by evaporation to give the3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-4-hydroxymethyl-2-methylpyrazoleas a colorless oil.

Alternatively, the3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-2-methyl-4-trityloxymethyl-pyrazolemay be dissolved in acetic acid and treated with hydrogen bromidewhereupon the trityl bromide is precipitated (and can be reused fortritylation) and the3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-4-hydroxymethyl-2-methylpyrazolewill remain in the acetic acid solution.

To a solution of 0.295 g of the above keto alcohol in 15 ml oftetrahydrofuran is added 0.230 g of thionyl chloride in 5 ml oftetrahydrofurane, followed by 0.160 g of pyridine in 5 ml oftetrahydrofuran. The mixture is stirred at room temperature for 30minutes and then treated with 10 ml of 1N hydrochloric acid. The organicphase is isolated, dried and evaporated to dryness yielding the4-chloromethyl-3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-2-methyl-pyrazoleas a colorless oil.

To a solution of the above chloroketone in 5 ml of dimethylformamide isadded an equivalent amount of potassium phthalimide. The mixture isstirred for 16 hours at room temperature and then diluted with diethylether. The organic solution is then washed with water and saturatedaqueous solution of sodium chloride. After drying over sodium sulfate,the ether solution is evaporated to dryness. The oily residue iscrystallized from diethylether to yield the3-[4-chloro-2-(2-fluoro-benzoyl)-phenyl]-4-phthalimidomethyl-2-methyl-pyrazole,m.p. 153°-155°.

EXAMPLE 7

The solution of 7.8 g of3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-2-methylpyrazole-4-carboxylicacid in 75 ml of methylene chloride and 6.7 ml diisopropyl ethylamine isstirred in an ice bath and 4.7 ml of thionyl chloride are added. Themixture is refluxed for 40 minutes, cooled and washed with icewater. Theorganic layer is dried, evaporated and the residue taken up in 65 ml oftetrahydrofuran and the solution saturated with ammonia. After stirringat 25° for 16 hours, the mixture is diluted in diethyl ether, washedwith water and brine, dried and evaporated. The resdiue is dissolved in300 ml of diethyl ether and the solution refluxed for 16 hours with 2 gof lithium aluminum hydride. After destroying the excess reagent andfiltering off the precipitate, the filtrate is washed with dilutedhydrochloric acid. The acidic layer is basified with aqueous sodiumhydroxide and extracted with methylene chloride. The extract is dried,evaporated, the residue taken up in ethyl acetate and the solutionacidified with hydrogen chloride, to yield the3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-4-aminomethyl-2-methylpyrazolehydrochloride melting at 260°-262°.

The starting material is prepared analogously as the 2-fluoro analog ofExample 6.77 g of3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-ethoxycarbonyl-2-methyl-pyrazoleare dissolved in 900 ml of ethanol and 240 ml of N aqueous sodiumhydroxide and the solution is refluxed for 2 hours. After cooling theaqueous phase is separated, washed with diethyl ether and acidified withhydrochloric acid. It is extracted with methylene chloride, the extractdried and evaporated. The residue is recrystallized from 200 ml ofdiethyl ether to yield the3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-2-methylpyrazole-4-carboxylicacid melting at 210°-213°.

EXAMPLE 8

The solution of 5.8 g of3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-2-methylpyrazole-4-carboxylicacid in 50 ml of methylene chloride and 5 ml of diisopropyl ethylamineis cooled in an ice bath, 3.5 ml of thionyl chloride are added and themixture is refluxed for 40 minutes. It is diluted with methylenechloride, quickly washed with ice-water, dried and evaporated. Theresidue is taken up in 50 ml of tetrahydrofuran, the solution saturatedwith methylamine and stirred over-night. The mixture is evaporated, theresidue taken up in methylene chloride and the solution washed withaqueous sodium carbonate. It is dried, evaporated and the residue takenup in 200 ml of diethyl ether and 1.2 g of lithium aluminum hydride areadded. The mixture is refluxed for 16 hours, decomposed with 1.2 ml ofwater, 1.2 ml of 15% aqueous sodium hydroxide and 3.6 ml of water, theprecipitate filtered off and the filtrate evaporated. The residue istaken up in ethanol, the solution neutralized with ethanolic oxalic acidand the precipitate collected, to yield the3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-4-methylaminomethyl-2-methylpyrazoleoxalate melting at 154° with decomposition.

EXAMPLE 9

The solution of 0.63 g of8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrazolo[4,3-d](2)benzazepine(U.S. Pat. No. 3,947,585, Example 4) in 15 ml of 5 N hydrochloric acidis refluxed for 24 hours and evaporated. The residue is recrystallizedfrom isopropanol-diethyl ether, to yield the5-chloro-2-(1-methyl-4-aminomethyl-3-pyrazolyl)-2'-chlorobenzophenonehydrochloride, showing a strong I.R.-band at 1682 cm⁻¹.

Analogously the5-chloro-2-(1-ethyl-4-aminoethyl-3-pyrazolylyl)-2'-chlorobenzophenonehydrochloride is obtained, melting at 170° with decomposition.

The starting material of the latter product is prepared as follows: Tothe solution of 1.5 g of8-chloro-6-(2-chlorophenyl)-1H,4H-pyrazolo-[4,3-d](2)benzazepine in 20ml of dimethylformamide, 300 mg of 50% sodium hydride in mineral oil(washed with hexane) are added and the mixture is stirred until thehydrogen evolution ceases. Thereupon 0.48 ml of ethyl iodide are addedand the mixture stirred at room temperature for 90 minutes. It isdiluted with diethyl ether, the organic layer washed with water andsaturated aqueous sodium chloride, dried and evaporated. The residue ischromatographed on silica gel and eluted with benzene-methanol (95:5),to yield the 8-chloro-6-(2-chlorophenyl)-2-ethyl-2H,4H-pyrazolo[4,3-d](2)benzazepine as the major fraction, melting at161°-163°.

EXAMPLE 10

The solution of 1 g of 8-chloro-6-(2-chlorophenyl)-1H,4H-pyrazolo-[4,3-d](2)benzazepine hydrochloride in 20 ml of 5 Nhydrochloric acid is refluxed for 24 hours and cooled to 0°. Theprecipitate formed is collected, to yield the5-chloro-2-(4-aminomethyl-3-pyrazolyl)-2'-chlorobenzophenonehydrochloride melting at 220° with decomposition.

I claim:
 1. A compound of the formula ##STR12## wherein Ph is1,2-phenylene and Ar is phenyl, both of said radicals are unsubstitutedor substituted by one or two of the same or different substituentsselected from the group consisting of lower alkyl, lower alkoxy, haloand trifluoromethyl, R_(o) is lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl,di-lower alkylamino-lower alkyl, Ar or Ar-lower alkyl, wherein theadditional chain-nitrogen or oxygen atom is separated from thering-nitrogen by at least 2 carbon atoms, each of R₁, R₂, and R₃ ishydrogen or lower alkyl, Am is amino, lower alkylamino or di-loweralkylamino, and X is oxo or thioxo; simple or mixed, open or cycliclower alkyl or alkylene ketals thereof; or a pharmaceutically acceptableacid addition salt thereof.
 2. A compound as claimed in claim 1, inwhich formula Ph is 1,2-phenylene, (lower alkyl)-1,2-phenylene, (loweralkoxy)-1,2-phenylene, (halo)-1,2-phenylene or(trifluoromethyl)-1,2-phenylene, Ar is H-Ph, R_(o) is lower alkyl,hydroxy-C_(m) H_(2m), lower alkoxy--C_(m) H_(2m), amino--C_(m) H_(2m),lower alkylamino--C_(m) H_(2m), di-lower alkylamino--C_(m) H_(2m) orH-Ph--C_(n) H_(2n), m is an integer from 2 to 4, and n such from 0 to 4,Am is amino, lower alkylamino or di-lower alkylamino, each of R₁, R₂,and R₃ is hydrogen or lower alkyl, and X is oxo or thioxo, or the simpleor mixed, open or cyclic lower alkyl or alkylene ketals thereof, or apharmaceutically acceptable acid addition salt thereof.
 3. A compound asclaimed in claim 1, in which formula Ph is 1,2-phenylene,(alkyl)-1,2-phenylene or (halo)-1,2-phenylene, Ar is H--Ph, R_(o) isalkyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 2-dialkylaminoethyl, 2- or3-dialkylaminopropyl or H-Ph-methyl, each of R₁, R₂, and R₃ is hydrogenor methyl, the group Am is amino o dialkylamino, X is oxo or thioxo orthe ethylenedioxy derivative thereof, in which compounds alkyl has 1 to4 carbon atoms, or a pharmaceutically acceptable acid addition saltthereof.
 4. A compound as claimed in claim 3, and having the formula##STR13## wherein R is hydrogen or methyl, R^(o) is methyl, ethyl, n- ori-propyl, n-, i- or t-butyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl,2-dimethylaminoethyl, 2- or 3-dimethylaminopropyl, 2-diethylaminoethyl,2- or 3-diethylaminopropyl or benzyl, each of R' and R" is hydrogen,methyl, fluoro or chloro and Am' is amino, dimethylamino ordiethylamino, the methyl or ethylene ketal or thioketal, or apharmaceutically acceptable acid addition salt thereof.
 5. A compound asclaimed in claim 4 and being the5-chloro-2-(1-methyl-4-aminoethyl-3-pyrazolyl)-2'-fluorobenzophenone, ora pharmaceutically acceptable acid addition salt thereof.
 6. A compoundas claimed in claim 4 and being the5-chloro-2-(1-methyl-4-aminoethyl-3-pyrazolyl)-2'-chlorobenzophenone, ora pharmaceutically acceptable acid addition salt thereof.
 7. A compoundas claimed in claim 4 and being the5-chloro-2-(1-ethyl-4-aminomethyl-3-pyrazolyl)-2'-chlorobenzophenone, ora pharmaceutically acceptable acid addition salt thereof.